Various steroids synthesized in the adrenal glands and gonads are capable of modulating neuron excitability in the CNS. For these compounds the term “neuroactive steroids” has been coined (Majewska et al., 1986), or “neurosteroids” for those that the brain can synthesize de novo (Baulieu, 1991).
Steroid hormones have long been recognized to have sedative, anesthetic and anti-seizure properties in animals and humans (Aird, 1944; Aird and Gordan, 1951; Gyermek et al., 1967; Green et al., 1978). Studies during the past two decades have uncovered that progesterone and deoxycorticosterone serve as precursors for the endogenous neurosteroids allopregnanolone (5α-pregnane-3α-ol-20-one) and THDOC (5α-pregnane-3α,21-diol-20-one), respectively (Reddy, 2003; 2009a). Testosterone-derived androgens such as androstanediol (5α-androstane-3α,17β-diol) and estradiol can be considered as neurosteroids (Reddy, 2008). Generally, the acute effects of neurosteroids are not related to interactions with classical steroid hormone receptors that regulate gene transcription. Moreover, neurosteroids are not themselves active at intracellular steroid receptors. They modulate brain excitability primarily by interaction with neuronal membrane receptors and ion channels, principally GABA-A receptors (Lambert et al., 2003; Reddy, 2003; Akk et al., 2009).
In addition to endogenous steroids such as pregnenolone sulfate, DHEA-S, estradiol, or progesterone for which neuroactive properties have been described (Paul and Purdy, 1992; Rupprecht, 1997), synthetic steroids have been developed recently that share their endogenous counterparts' characteristic of modulating a variety of G-protein-coupled receptors and ligand-gated ion channels (Gasior et al., 1999).
Some synthetic neurosteroids that show better pharmacokinetics and efficacy are evaluated for sedative and anxiolytic (minaxolone), anesthetic (alphaxolone) and antiepileptic (ganaxolone) effects.
However, the diverse in vivo actions of neuroactive steroids depend on the lack of specificity of natural and synthetic steroids that do not bind uniquely to one neurotransmitter receptor but on several of them. The metabolism of neuroactive steroids with metabolites that exhibit different pharmacological profiles compared to their precursors is also responsible for the variety of effects of a single steroid. As yet, no derivatives of naturally occurring or synthetic steroids have been developed that show exclusive receptor specificity or avoid side effects due to it metabolization.